Renal Transplantation in the Elderly - nEverOld Study

Immunosuppression in Renal Transplantation in The Elderly: Time to Rethink. - nEverOld Study

An exploratory study of the efficacy and safety of a regimen consisted of Everolimus plus low tacrolimus for the immunosuppression in renal transplantation in the elderly.

To evaluate the pharmacokinetics of immunosuppressants that have been little studied in this population.

To evaluate whether the polymorphism of the genes that determine the expression of metabolizing enzymes and transporters of xenobiotics interfere in the elderly, also in the younger population, absorption and metabolism of immunosuppressants.

To evaluate the potential minimization of immunosuppression in this population refers to how does the re-population of peripheral lymphocytes, in this age group, after the use of lymphocyte-depleting agents such as thymoglobulin and subsequently maintained with two regimes.

Clarify which markers of renal filtration exist today, cystatin C and serum creatinine, is the right to monitor renal function in elderly transplanted.

Study Overview

• Status: Unknown
• Conditions: Renal Transplant Rejection; Graft Failure; Transplant; Failure, Kidney; Chronic Renal Failure (CRF)
• Intervention / Treatment: Drug: Everolimus

Detailed Description

Objectives: The objective of this study is to evaluate the safety and efficacy of everolimus (EVL) combined with low dose of Tacrolimus in comparison with Mycophenolate Sodium (MPS) combined with standard dose of Tacrolimus as immunosuppressive therapy for elderly recipients of kidney transplantation.

Comparison between the two study arms of:

Primary Objective:

1. Composite efficacy failure demonstrated by graft loss and/or death with functional graft and/or GFR (Glomerular Filtration Rate determined by EDTA-Cr51) < 50 ml/min at the end of first year after transplantation and every year until the fifth year.

Secondary Objectives:

1. Pharmacokinetic study of immunosuppressive drugs (Tacrolimus, Everolimus and Mycophenolate Sodium) in the study population at days 7, 30, 60, 67, 90 and 180 post-transplant.
2. Serious adverse events (as internationally defined by ICH-GCP) every year, for five years.
3. Biopsy proven acute rejection rated every year, for five years.
4. Identify which of the renal filtration markers existing today, Cystatin C or Serum Creatinine, is more adequate to monitor renal function in elderly transplant and to develop abbreviated equations for eGFR from day 7 on.
5. Evaluation of other metabolic effects (bone density at month 12 post-transplant; vitamin D at months 2 and 12 post-transplant; and gonadal function at months 1 and 12 post-transplant) and Quality of Life at months 1, 12, 18, 24, 36, 48 and 60 post-transplant in the study population.
6. Left Ventricular Mass (LVM) and Left Ventricle Ejection Fraction (LVEF) measured by echocardiography at the end of the first year.

• Study Type: Interventional
• Enrollment (Anticipated): 90
• Phase: Phase 4

Contacts and Locations

Study Locations

• Brazil
  • SP
    • Sao Paulo, SP, Brazil, 05403900
      • Recruiting
      • Clinical Hospital of the School of Medicine, University of Sao Paulo
      • Principal Investigator: Elias David-Neto, PhD
      • Sub-Investigator: Francine B. Lemos, PhD
      • Sub-Investigator: Nelson Z. Galante, PhD
      • Sub-Investigator: Fabiana Agena, MS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• All renal (only) male and female recipients aged ≥ 60, years undergoing kidney transplantation from a living or deceased donor, including Expanded Criteria Donors (ECD).
• Panel Reactive Antibody (PRA) < 30%.
• Patients who consented to participate in the study by signing the informed consent form before the transplant surgery to the 1st post-operative day).

Exclusion Criteria:

• Allergy to any of proposed medications
• Patients with any active infection including HBV, HCV and HIV.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Everolimus; Number of patients: 45 Everolimus: initial dose of 1 mg BID. Doses will be adjusted in order to maintain Everolimus whole blood trough concentrations between 3-8 ng/ml. Tacrolimus: initial dose of 0.1 mg/kg/day. Doses will be adjusted in order to maintain Tacrolimus whole blood trough concentrations between 2- 4 ng/ml thereafter. Corticosteroids: as clinical practice.

Drug: Everolimus; This is a 5-years prospective, randomized, exploratory, single-center, parallel group trial that includes renal transplanted elderly patients (≥ 60 years old) randomized between months 1 and 3 after transplantation to be maintained under MPS/TAC regimen or be switched to EVL/low-TAC. Everolimus: initial dose of 1 mg BID. Doses will be adjusted in order to maintain Everolimus whole blood trough concentrations between 3-8 ng/ml. Tacrolimus: initial dose of 0.1 mg/kg/day. Doses will be adjusted in order to maintain Tacrolimus whole blood trough concentrations between 2- 4 ng/ml thereafter. Corticosteroids: as clinical practice.; Other Names: Certican (NOVARTIS); Myfortic (NOVARTIS); Prednisone (generic)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of functional graft	Composite efficacy failure demonstrated by graft loss and/or death with functional graft and/or GFR (Glomerular Filtration Rate determined by EDTA-Cr51) < 50 ml/min at the end of first year after transplantation and every year until the fifth year.	The study is planned to analyze all patients at the end of the fifth year after transplantation. However, an interim analysis will be done at the end of each year.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic of Tacrolimus	Pharmacokinetic of Tacrolimus in the study population at days 7, 30, 60, 67, 90 and 180 post-transplant.	Days: 7, 30, 60, 67, 90, 180.
Serious adverse events	Evaluate serious adverse events (as internationally defined by ICH-GCP).	Every year, for five years
Biopsy	Biopsy proven acute rejection rated every year, for five years.	Every year, for five years
Renal filtration markers	Identify which of the renal filtration markers existing today, Cystatin C or Serum Creatinine, is more adequate to monitor renal function in elderly transplant and to develop abbreviated equations for eGFR from day 7 on.	Days: 7, 30, 37, 60, 67, 90, 180. Months: 12, 18, 24, 36, 48, 60
Bone density	Evaluation of bone density at month 12 post-transplant.	Month 12
Vitamin D	Evaluation of vitamin D at months 2 and 12 post-transplant.	Months: 2, 12.
Gonadal function	Evaluation of gonadal function at months 1 and 12 post-transplant.	Months: 1, 12.
Quality of Life	Evaluate Quality of Life at months 1, 12, 18, 24, 36, 48 and 60 post-transplant in the study population.	Months: 1, 12, 18, 24, 36, 48, 60.
Left Ventricular Mass (LVM)	Left Ventricular Mass (LVM) measured by echocardiography at the end of the first year.	Month: 12.
Left Ventricle Ejection Fraction (LVEF)	Left Ventricle Ejection Fraction (LVEF) measured by echocardiography at the end of the first year.	Month: 12.
Pharmacokinetic of Everolimus	Pharmacokinetic of Everolimus in the study population at days 7, 30, 60, 67, 90 and 180 post-transplant.	Days: 7, 30, 60, 67, 90, 180.
Pharmacokinetic of Mycophenolate Sodium	Pharmacokinetic of Mycophenolate Sodium in the study population at days 7, 30, 60, 67, 90 and 180 post-transplant.	Days: 7, 30, 60, 67, 90, 180.

Collaborators and Investigators

• Sponsor: University of Sao Paulo General Hospital
• Investigators: Principal Investigator: Elias David-Neto, PhD, Clinical Hospital of the School of Medicine, University of Sao Paulo

Publications and helpful links

General Publications

• Romano P, Agena F, de Almeida Rezende Ebner P, Massakazu Sumita N, Kamada Triboni AH, Ramos F, Dos Santos Garcia M, Coelho Duarte NJ, Brambate Carvalhinho Lemos F, Zocoler Galante N, David-Neto E. Longitudinal Pharmacokinetics of Mycophenolic Acid in Elderly Renal Transplant Recipients Compared to a Younger Control Group: Data from the nEverOld Trial. Eur J Drug Metab Pharmacokinet. 2019 Apr;44(2):189-199. doi: 10.1007/s13318-018-0506-6.

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (Actual): July 1, 2014
• Study Completion (Anticipated): June 1, 2019

Study Registration Dates

• First Submitted: June 21, 2012
• First Submitted That Met QC Criteria: June 26, 2012
• First Posted (Estimate): June 28, 2012

Study Record Updates

• Last Update Posted (Estimate): December 4, 2015
• Last Update Submitted That Met QC Criteria: December 3, 2015
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: elderly; kidney transplantation; pharmacokinetic; everolimus; tacrolimus; immunosuppressive therapy; Cystatin C; biopsy; chronic renal failure; metabolic effects; mycophenolate sodium; serious adverse events; Left Ventricular Mass (LVM); Left Ventricle Ejection Fraction
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Renal Insufficiency; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Cathartics; Prednisone; Everolimus; Lactitol
• Other Study ID Numbers: 26423